Even though the Vancouver meeting is just past, ISEH leaders are hard at work preparing the program and accepting award nominations for the 41st Annual Scientific Meeting, 23-26 August, 2012, at the Hotel Okura, Amsterdam, Netherlands. Meeting Chair Elaine Dzierzak, Ph.D., Erasmus Medical Center Cell Biology Department, Rotterdam, Netherlands, is at the helm of a strong committee comprising hematology and stem cell experts from six countries. They are looking to build robust discussion around topics such as reprogramming and epigenetics, HSC biology, progenitor cell biology, microenvironment, aging, transplantation/gene therapy/regenerative medicine, leukemia, lymphoma, developmental biology, tissue inflammation and genomics. Also, they are scouring the evaluations from the Vancouver meeting to respond to attendee comments. Abstract submissions will open in February.

ISEH recently accepted 2012 nominations for:

McCulloch & Till Award Established in 2004 in honor of Professor Ernest McCulloch and Professor James Till, this award recognizes junior scientists in the field of hematology and stem cells.

Donald Metcalf AwardEstablished in 1999 in honor of Professor Donald Metcalf "the father of hematopoietic cytokines" for his pioneering work on the control of blood cell formation, this award recognizes distinguished scientists in the field.

Winners will be announced on the website and in the February 2012 Connections newsletter.

Vancouver Sets the Bar High for Amsterdam From award winner lectures and new investigator sessions to posters and a cartoonist, the 40th Annual Scientific Meeting in August had much to offer. The evaluations completed by meeting attendees showed:

97% of attendees were "highly satisfied” or "satisfied”

94% of attendees rated the scientific format of the meeting "excellent” or "good”

93% of attendees would recommend this meeting to others

Among the things attendees liked most about the 2011 meeting were hearing great talks, meeting old friends, talking with younger investigators, excellent scientific quality, meeting size and the combination of invited speakers and oral presentations in the same session. Comments about what attendees liked least included simultaneous sessions, abstract book, short time for posters and lack of exhibitors.

"As always, the quality of the submitted abstracts was incredibly high, which led to a very strong scientific program,” summarizes Gerald de Haan, ISEH president and 2012 meeting chair. "This also applied to the poster sessions, which were very lively, but too short. The invited speakers this year consisted of quite a few investigators that had not been at the ISEH before, and offered a great variety of topics related to experimental hematology. So, beyond the usual suspects there were many new groups represented. Again, as always, the ISEH is a meeting where most attendees do not come in only to give a talk and leave, but rather stay for the entire meeting. In Vancouver, the very last session on developmental hematology was one of the busiest and liveliest sessions. This will be difficult to beat in Amsterdam….”

A fun twist in Vancouver was local cartoonist Jesse van Muijlwijk who sat in on some of the sessions and a reception, drawing away. A few of his cartoons appear below.

Thank you to the 2011 ISEH Meeting exhibitors, sponsors, and grant supporters:

Experimental Hematology

Take a quick tour of the September and October issues and get a feel for the great scientific content. Read the full issues.

In this Issue – September 2011

MicroRNAs in myelodysplastic syndrome (MDS) Erdogan et al Accumulating data suggest that miRNAs may contribute to development of MDS. Most recently, it has been shown that the knockdown of miR-145 and miR-146a recapitulates the thrombocytosis and dysmegakaryopoiesis seen in the 5q- syndrome subtype of MDS in mice. In this study, Erdogan et al present the first microarray profiling of miRNA expression in MDS using both discovery and validation sets, and demonstrate decreased expression of 8 miRNAs (miR-103, miR-140, miR-150, miR-342, miR-378, miR-483, miR-632 and miR-636) in 42 MDS patients. In corroboration with the miRNA signature, they show overexpression of c-Myb, (a gene essential for self-renewal of HSCs in mice and zebrafish), the predicted regulatory target of miR-103, miR-150 and miR-342, and the differential expression and localization of the hedgehog pathway tumor suppressor Sufu, the predicted target of miR-378. These findings further support the importance of miRNAs in MDS and suggest that miRNA expression profiling may be used as a novel diagnostic tool, as well as help design targeted therapeutics for MDS patients.

Cellular therapies: emerging therapeutic tools to treat hematological malignanciesSuck et al and Niam et al Natural killer (NK) cells (CD56+CD3-) are potent in killing major histocompatibility complex class I negative targets in a broad range of malignancies, and therefore are promising candidates for adoptive immunotherapy. Protocols that provide large numbers of functional NK cells are required. In their first study, Suck et al showed that IL-15, a novel cytokine for NK cell activation and survival, is able to support large-scale expansion of clinical grade lymphokine-activated killer cells (LAK-NK) in long term cultures, at similar levels achieved by IL-2 (traditionally used for NK cell activation). Interestingly, at later time points in culture, cells expanded in IL-15 had superior cytotoxicity against hematological targets than cells generated in IL-2. Cytokine-induced killer (CIK) cells, also used for adoptive immunotherapy, are cytokine activated T cells (CD56+CD3+) with major histocompatibility complex–unrestricted killing properties against lymphoma, chronic myeloid leukemia and acute myeloid leukemia cells. In the second study from the same group, Niam et al show the feasibility of clinical scale expansion of CIK cells from healthy donors and leukemia patients at various stages of treatment, some recovering from chemotherapy and some with circulating leukemic cells. Both of these studies will facilitate the clinical application of LAK-NK or CIK cells for adoptive immunotherapies in various malignancies.

In this Issue – October 2011

Sox genes in zebrafish hematopoiesisChung et al Hematopoietic programs are largely conserved between mammals and zebrafish; therefore zebrafish has emerged as a model system for studying hematopoiesis during embryonic development. Moreover, the zebrafish transparent embryo develops outside the mother's body, and is easily accessible to genetic manipulation. In this study, Chung et al demonstrated, for the first time, the distinctive roles of SoxF genes (a group of transcription factors sharing HMG box domain) in zebrafish embryonic hematopoiesis. They showed that sox17 was important in maintaining primitive hematopoiesis, and unlike in mouse, did not have any effect on definitive hematopoiesis. Both sox7 and sox18 regulated angiogenesis and vasculogenesis, and sox32 had an impact on both vascular development and definitive hematopoiesis. Future studies reporting whether these findings have any relevance to human diseases will be very informative.

Targeting two may be better than one for refractory Hodgkin Lymphoma (HL) Jóna et al Patients with relapsed or refractory HL have a poor prognosis, and they urgently need novel therapeutic interventions. Histone deacetylases regulate a wide range of cellular functions, such as cell survival, cell cycle progression, angiogenesis, and immunity, and therefore, their inhibitors have become promising agents to be incorporated into standard chemotherapy regimens. One such inhibitor, SNDX-275 (Entinostat, an oral class 1 isoform–selective histone deacetylase inhibitor), is in clinical trials for treatment of advanced breast and lung cancers. In this study, Jóna et al showed that SNDX-275 had a potent antiproliferative activity in HL-derived cell lines by directly inducing apoptosis through the activation of the intrinsic caspase pathway in a dose- and time-dependent manner, and indirectly by affecting the tumor microenvironment and immunity through the regulation of cytokines and chemokines. The antiproliferative effects of SNDX-275 were further enhanced when combined with Bcl-2 inhibitors (ABT-737 and obatoclax). Based on these favorable pre-clinical activities, the investigators initiated a phase II study to determine the safety and efficacy of SNDX-275 as a single agent in patients with relapsed HL. Studies combining SNDX-275 with Bcl-2 inhibitors may soon become available for patients with various malignancies.

miRNAs: diagnostic tools and therapeutic targets Ovcharenko et al MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Recent studies have shown that microRNA expression can be increased and or silenced in acute myeloid leukemia (AML) and this can influence clinical outcome in patients. These studies have also suggested that alterations in a single miRNA or miRNA signatures not only can provide additional diagnostic and prognostic tools, but can also serve as potential therapeutic targets. For instance antileukemic effects can be achieved in mice by restoring miR-223 and miR-29b expression using a hypomethylating agent, decitabine. A phase 1 clinical trial testing the safety of intravenous administration of antimiR-122 in healthy volunteers is ongoing in Europe. Mutations of the nucleophosmin (NPM1) gene are the most common genetic alteration in cytogenetically normal AML patients and account for one-third of adult AML patients. Even though these patients have very distinct features and a favorable prognosis, additional markers will be beneficial to improve risk stratification in these patients. In this study, Ovcharenko et al demonstrated that miR-10a is specifically overexpressed in NPM1 mutant AML samples, confirming what previously was documented by another group. They identified MDM4 as a target of miR10a, and demonstrated an inverse relationship between miR10a and MDM4 expression in leukemic cells. MDM4 is a critical negative regulator of the p53 signaling pathway and may collaborate with NPM1, another important regulator of the pathway and perhaps collectively contributing to leukemogenesis in NPM1 positive patients. It is reasonable to predict that miRNA expression profiling may become a widely used diagnostic tool, as they will continue providing therapeutic targets that would facilitate the development of novel microRNA-based treatment strategies in AML and other malignancies.

Transcriptional control mechanisms in hematopoiesis: the impact of high-throughput sequencing technologiesWilson et alTranscription factor (TF) proteins are major regulators of blood stem cell development and differentiation into the multiple lineages. Many leukemias harbor acquired mutations in the TF genes suggesting that their activity is tightly regulated to achieve a fine balance between maintenance of normal hematopoietic function and prevention of the development of hematologic malignancies. In their very comprehensive review, Wilson et al summarized the new insights gained from ChIP-Seq studies into transcriptional control mechanisms in hematopoiesis (erythroid cells, hematopoietic stem/progenitor cells, megakaryocytes and lymphoid cells) and leukemogenesis. They also addressed some of the technological and organizational challenges that slow down the full exploitation of the potential power of ChIP-Seq analysis to advance our understanding of hematopoietic transcriptional control mechanisms.

A Vancouver meeting New Investigator session saw Margaret Goodell, Baylor College of Medicine: Shannon McKinney‐Freeman, St. Jude’s Children’s Hospital; and Michael Heuser, Hannover Medical School, combining to discuss strategies for landing that much-desired job in academia. The team covered the numerous preparatory steps that need to happen to offer the best chance for success. It begins with identifying opportunities. "You have to know yourself and what you want,” shared McKinney-Freeman. "There are the obvious questions like are you OK with teaching? Are you restricted geographically? Do you want to interact with clinicians? Do you want access to graduate students? Big city? Research hospital?” McKinney-Freeman advised that those seeking positions must create their own opportunities. Of course you must scour the job postings, she said, but it takes more. She suggested asking your graduate and postdoctoral mentors to contact colleagues on your behalf or putting yourself in positions to meet senior colleagues at meetings and conferences. Goodell offered some insight from the hiring end of the spectrum and talked about search committee strategies to select the appropriate candidate. She indicated that, of course, applications are the first screen. "Every typo matters,” she warned. "Every review, paper and reference counts.” From that initial screen, 10 to 14 candidates make the cut and further research is done on each before anyone comes in for an interview. This may include one or more telephone calls to the candidate to check on status of publications or to see how the conversation feels. She stressed the importance of thorough and careful work on everything sent in. If you are fortunate to be invited for a visit, the quality of your talk and interactions are of utmost importance. Equally important is ascertaining mutual interest level – you for the program and the program for your skills. Feedback is obtained from everyone you meet that day. The second visit is designed to further assess your fit for the position. Goodell warns that being invited for the second visit is not a guarantee of an offer – you can still win or lose at this stage. Heuser provided the M.D. perspective, as a doctor practicing in Germany, and talked about the path to research independence. After the Ph.D./M.D. degree and postdoc training, he encouraged candidates to make the most of their "transition phase.” "A mentor is good, but a patron is better,” he shared. He then went on to talk about creating your own position by securing your own funding and offered some good places to seek that funding. He stressed doing your homework, as each funding organization has specific requirements for applications. Take a look at the slides from this presentation in the New Investigator section of the ISEH website. The web page includes numerous other resources.

Congratulations to Vancouver Winners

Akanksha Chhabra, Alessandro Di Tullio and Amélie Montel-Hagen received New Investigator Awards for the presentations at the 40th Annual Scientific Meeting in Vancouver. Thank you for sharing your discoveries with the ISEH community.

Society News

It’s Dues Renewal Time!

The New Year is right around the corner, and you will want to be sure your ISEH membership is uninterrupted by renewing today. Membership dues are paid on a calendar year (January 1 through December 31) according to the following categories:

Active member - $175: Any scientist engaged in the study of hematology and stem cell research qualifies for membership.

Associate/Member in Training - $65: Any student registered in a university or college of higher learning or post-doctoral fellow may join as an associate member.

Not yet a member? We invite all individuals interested in the field of experimental hematology including hematopoiesis, oncology, immunology, stem cell biology, transplantation and cell and gene therapy to join ISEH and reap the benefits which include:

Easy access to more than 800 members, your colleague researchers in the field A personal subscription and exclusive full-text online access to the journal, Experimental Hematology, including supplements and abstracts for ISEH-supported meetings.

Reduced registration fees at the ISEH Annual Scientific Meeting and other selected educational events organized or supported by ISEH.

Eligibility for ISEH awards and travel grants.

Full access to enhanced website. You are now connected through instant messaging to members who are online, posting to colleagues’ walls, reading articles on featured membership profiles and responding to discussion forums.

An opportunity to serve on ISEH Committees and the Board of Directors.

When you renew on the ISEH website, be sure to also update your member profile, so that members and staff know how to reach you.

I recently enjoyed the privilege of participating in a small "think tank” sponsored by amfAR, The Foundation for AIDS Research. The topic was "Promotion of the in vitro amplification of genetically-modified stem cells as an approach to defining a practical cure for AIDS.”

The meeting held outside Philadelphia in early September brought together a small group of scientists and clinician-scientists spanning expertise in AIDS, gene therapy and hematopoietic stem cells. Notably, several of the 14 participants were well known to our membership with the likes of Irvin Bernstein (Fred Hutchinson Cancer Research Center), Hans-Peter Kiem (Fred Hutchinson Cancer Research Center) and Faiyaz Notta (a postdoctoral fellow from John Dick’s laboratory, University of Toronto).

Their participation highlighted to me something that I have mentioned in recent editorials in our journal – this being the sense that the field of experimental hematology is enjoying a relevancy and vibrancy that makes for an exciting time. In this instance the convergence of advances in methods for stem cell expansion, many coming from members of our society, and gene therapy approaches based on genetic manipulation of hematopoietic repopulating cells, is creating momentum and a sense of optimism for cure of such a devastating health problem as AIDS.

Of course the reality, and the major outcome of such a meeting, is a realization that many questions remain to be addressed. Do we yet have the agents and culture platforms needed for clinical scale expansion of repopulating cells? Do we have the necessary assays for clinically relevant repopulating cells short of clinical trials? Do we understand the complexity and heterogeneity of the stem cell compartment in sufficient detail to know which stem cell needs to be expanded, and how to achieve this? Do we understand the molecular regulation of self-renewal in sufficient detail to identify the "ideal” stimulator? A long list of still unanswered questions also emerged in the context of having the right targets and tools to block HIV infection.

Despite the many questions, and unlike for the direction of the stock market, I think we can confidently predict that these and related questions are and will remain top of mind for many in our society and that we can look forward to an increasing pace of breakthroughs where the worlds of stem cells and gene therapy collide.

ISEH, comprised of industry leaders in hematology, immunology, stem cell research, and cell and gene therapy, connects members worldwide for the opportunity to advance scientific knowledge. Each issue of Connections in Hematology & Stem Cells will introduce you to those members. This issue, meet Margaret "Peggy” Goodell, Ph.D., Baylor College of Medicine.

Margaret "Peggy” Goodell, Ph.D., is ISEH vice president and serves on the 2012 Scientific Program Committee. She has been on the faculty of the Baylor College of Medicine since 1997.

Her route to Baylor included some very interesting stops. Undergrad work was split between two continents – starting at Wesleyan University, Middletown, CT, USA and finishing at the Imperial College of Science and Technology in London, England. Goodell’s Ph.D. was achieved at the University of Cambridge, Cambridge, England.

"While looking for post-doctoral positions from graduate school, I was very interested in the future of cell and gene therapy,” Goodell recounts. "I realized that hematopoietic stem cells (HSC) were the key to long-term therapy of blood diseases, so I sought out Richard Mulligan's lab, for his combined interest in stem cells and gene therapy. Very few labs were interested in any kind of stem cells, so I was fortunate to find a small niche where their promise was recognized. There, my goal was to learn how to make HSCs replicate without differentiating, which I saw as critical to using them therapeutically. While no lab has yet achieved this goal, it led me to identify the Hoechst dye efflux properties of stem cells, and a new way to purify them. I have continued to use the "side population" purification strategy, refining it over time, as I have investigated the genes that regulate the normal function of HSCs.”

Mulligan’s lab was at the Whitehead Institute for Biomedical Research and Harvard Medical School, Cambridge, MA, USA. From there, she moved to Baylor. Goodell’s current work is focused on the regulation of normal HSCs, and what goes awry in cancer. She is particularly interested in how epigenetic mechanisms, specifically DNA methylation, control HSC self-renewal and differentiation. Recent entries in a long list of published manuscripts include "CD81 is essential for the re-entry of hematopoietic stem cells to quiescence following stress-induced proliferation via deactivation of the Akt pathway” in PLoS Biology and "Irgm1 protects hematopoietic stem cells by negative regulation of IFN signaling” in Blood.

In addition to her research, a rewarding part of Goodell’s work is the opportunity to work with those early in their careers and assist them in moving forward. Goodell directs a laboratory of about 20 students and post-doctoral fellows.

"At the 2011 ISEH meeting, I gave a workshop on academic career development,” she shares. "It was a thrill for me to present the workshop alongside Shannon McKinney-Freeman, who was my first graduate student, and now has an independent faculty position at St. Jude's Children's Hospital.”

In addition to her ISEH involvement, Goodell has served on the board of the International Society for Stem Cell Research (2005-2008), and on the Scientific Committee for Stem Cells for the American Society of Hematology (2009-2012). She currently is on the editorial boards of Cell Stem Cell and PLoS Biology, and serves as a reviewer for multiple journals and granting agencies.

She points to the tight funding situation as the biggest challenge facing academia today.

"The tight funding situation will slowly force changes in the way we do science,” she notes. "Universities and medical schools will have to adapt their expectations of the purpose of their stable of scientists, and we may see fewer trainees and more professional staff with time. As these changes will evolve slowly, we will have to anticipate and adapt to them in advance, or even better, lead them.”

While deeply involved with her work, Goodell strikes a balance by being equally as involved in the lives of her three young daughters, ages 11, 9 and 7.

"With them I get to dabble in lots of activities, such as re-learning the joys of things like poetry, history, algebra, Latin, piano and art,” she says. "Someday I might resume my personal hobbies, such as photography and exotic travel!”

ISEH members: Connect with Peggy through the ISEH member database. Click here to learn more about her or to build your personal profile. You can also learn more about the Goodell lab.